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Aplastic Anemia

Aplastic anemia (AA), the paradigm of the bone marrow (BM) failure syndromes, is most simply defined as peripheral blood pancytopenia and a hypocellular BM ( Fig. 31.1 ). AA occurring as a primary hematologic disorder is historically denoted idiopathic, but it is now understood as immune-mediated. Constitutional marrow failure syndromes share a similar pathology of an apparently “empty” marrow (see Chapter 30 ) and can be…

Inherited Bone Marrow Failure Syndromes

Introduction Inherited bone marrow (BM) failure is defined herein as decreased production of one or more of the major hematopoietic lineages; i.e., red blood cells (RBCs), neutrophils, and platelets, due to germline mutations that were derived from the parents or occurred de novo ( Table 30.1 ). Although outdated, the term “constitutional” has been used interchangeably with “inherited” and similarly implies that a genetic abnormality causes…

Thrombocytopoiesis

Platelets, once regarded simply as ”blood dust,” are now recognized to play essential roles in hemostasis. Not only do they form a hemostatic plug and initiate thrombus formation in the event of vascular injury, but they also repair minute vascular damage that occurs on a daily basis. Platelets also participate in wound healing and angiogenesis via the delivery of key growth factors to sites of vascular…

Granulocytopoiesis and Monocytopoiesis

Granulocytopoiesis Granulocytes (neutrophils, eosinophils, and basophils) are short-lived cells that are critical to both antimicrobial and inflammatory responses. The bone marrow (BM) produces granulocytes, particularly neutrophils, at a prodigious rate to supply the baseline need for circulating cells that survive in the peripheral blood for only 3 to 24 hours. It also has the capacity to sharply increase granulocyte production in response to a wide range…

Biology Of Erythropoiesis, Erythroid Differentiation, And Maturation

The production of erythroid cells is a dynamic and exquisitely regulated process. The mature red cell is the final phase of a complex but orderly series of genetic events that is initiated when a multipotent stem cell commits to the erythroid program. Expression of the erythroid program occurs several divisions later in a greatly amplified population of erythroid cells, which have a characteristic form and structure,…

Treatment of Hematologic Malignancies With Genetically Modified T Cells

Conventional modalities for treating cancer remain unsatisfactory. Despite the introduction of small molecules that target specific molecular lesions or pathways within the cancer cells, cure rates for many common tumors remain low, while adverse events are still distressingly high. Cancer immunotherapy represents a promising extension of highly targeted cAncer therapy with potentially favorable toxicity and pharmacoeconomic profiles. Until recently, most attention has been on the development…

Unmodified Ex Vivo Expanded T Cells

T lymphocytes have the natural ability to destroy viral-infected or tumor target cells by a range of mechanisms that are initiated upon recognition of target peptides presented by histocompatibility antigens. Coupled with their ability to traffic through multiple tissues and self-renew, these properties make T lymphocytes an appealing cell-type for adoptive immunotherapy of cancer. Allogeneic hematopoietic stem cell transplantation (HSCT) is enduring “proof-of-principle” for adoptive immunotherapy…

T-Cell Immunity

Thymus-derived lymphocytes (T cells) play an essential role in the immune response to pathogens and against host cells that have undergone malignant transformation. T cells are critical regulators of the immune system that act through production of soluble mediators and direct interactions between ligands on the T-cell surface and receptors on other immune cells. This chapter reviews T-cell activation after engagement with specific antigens and describes…

Complement And Immunoglobulin Biology Leading To Clinical Translation

Complement and immunoglobulins represent the two major arms of humoral immunity and are discussed in detail in respective major subsections of this chapter. The complement section begins with a comprehensive overview of pathway activation, regulation, and effector mechanisms, followed by discussion of the pathological consequences of various complement deficiencies and polymorphisms. Next discussed is complement’s integral role in B-cell and T-cell immunity. Additional topics include the…

B-Cell Development

B lymphocytes are the subset of white blood cells specialized to synthesize and secrete immunoglobulin (Ig). Their name derives from the finding that the avian b ursa of Fabricius is a site of B-cell production. However, post-natal B-cell production in mammals takes place in the bone marrow. Following their production, newly generated B lymphocytes migrate into secondary lymphoid organs such as the spleen where they undergo…

Natural Killer Cell Immunity AND THERAPY

Natural killer (NK) cells are large, granular lymphocytes that comprise about 10% to 15% of the circulating peripheral blood lymphoctyes. These unique cells were first characterized by their ability to lyse targets independently of activating or initiating stimuli. NK cells are a critical cellular component of the innate immune system that have the ability to target and lyse malignant and virally infected cells. In addition, NK…

Dendritic Cell Biology

Dendritic cells (DCs), originally discovered in 1973 by Ralph M. Steinman and Zanvil A. Cohn and named after their distinct stellate morphology, are important regulators of immune responses. Specialized in antigen acquisition, processing, and presentation, the hallmark of DCs is their ability to induce naïve T cell activation and effector differentiation. DCs also interact with other immune cells, such as B cells, natural killer (NK) cells,…

Aging and Hematopoiesis

Aging Increase in life expectancy has resulted in a major demographic global shift toward an elderly population. As a consequence, the prevalence of a multitude of age-associated diseases has increased gradually during the last decades, resulting in an increased number of hospitalizations of elderly individuals. A better understanding of the mechanisms that cause aging is crucial in order to mitigate age-associated clinical conditions. Multiple “hallmarks” of…

Cell Death

Core Apoptosis Pathways Apoptosis is a biochemically well-defined programmed cell death that is essential for normal development and cellular homeostasis; dysregulation of apoptosis is involved in several diseases. The classical morphological features of apoptosis include cell shrinkage, membrane blebbing, nuclear condensation, and deoxyribonucleic acid (DNA) fragmentation. The biochemical hallmarks of apoptosis include permeabilization of the outer mitochondrial membrane (MOMP), activation of caspases, and the externalization of…

Control of Cell Division

The Cell Division Cycle The mammalian cell cycle is divided into four phases: mitosis (M), deoxyribonucleic acid (DNA) synthesis (S), and the gap phases G1 and G2 ( Fig. 17.1 ). Mitosis is recognized when cells visibly undergo cell division and chromatin becomes condensed, sequentially progressing through prophase, metaphase, anaphase, and telophase. The G1 phase occurs immediately after mitosis has been completed and ends when DNA…

Current Biology of Stem Cell Homing and Mobilization: Dynamic Interactions Between Hematopoietic Stem and Progenitor Cells and Their Surrounding Bone Marrow Microenvironment

Introduction Hallmarks of hematopoietic stem and progenitor cell (HSPC) function include their dynamic metabolism, active bi-directional migration (bone marrow [BM] homing, egress, recruitment, and mobilization to the blood), durable multilineage BM and blood repopulation potential, self-renewal and chemotherapy resistance. Hematopoietic stem cells (HSCs) mainly reside in the BM, and their chemotherapy resistance requires their quiescence, adhesion, and metabolic interactions with bone-forming stromal cells. However, HSPCs are…

Cell Adhesion

Cell adhesion is essential for the development and maintenance of multicellular organisms. Cell-to-cell and cell-to-matrix adhesion provide a mechanism for intercellular communication and to define the three-dimensional architecture of organs. The regulated nature of cell adhesion is particularly evident in the hematopoietic system, where blood cells routinely make transitions between nonadherent and adherent phenotypes during differentiation, and in response to stimuli in the circulation or extravascular…

Hematopoietic Microenvironment

Evolution of the Niche Concept In 1868, Ernest Neumann first suggested that blood cells are being replenished throughout postnatal life, and this proposal led to the attempts to localize the place of hematopoiesis. His hypothesis that blood cell production takes place in the bone marrow (BM) was experimentally validated by selective lead shielding of limbs in irradiated animals almost a century later. Notably, these and other…

Stem Cell Model of Hematologic Diseases

Cell-Of-Origin Studies in Hematologic Malignancies One of the prevailing models of cancer development proposes that a cancer is initiated and maintained through the function of CSCs, which represent a rare population of cells within a cancer that have an indefinite proliferative potential and are ultimately responsible for the generation of the bulk of cancer cells. This so-called CSC hypothesis has been best studied in hematopoietic malignancies.…

Role of Chemokines in Leukocyte Trafficking

The mammalian immune system has evolved to mount multifaceted molecular and cellular microbicidal responses tailored and custom-adapted to eliminate an endless variety of infectious agents and, at the same time, remain tolerant to self-antigens. Accomplishing these tasks requires continuous tightly controlled movement of billions of motile immune cells that roam throughout the body along distinct nonrandom traffic routes from one tissue to another using blood and…